Berry-derived Bioactive Compounds as Chemopreventive Agents in Colorectal Cancer: Molecular Mechanisms and Gut Microbiota Interactions.

Berry-derived bioactive compounds are increasingly recognized as promising chemopreventive agents for colorectal cancer (CRC). CRC develops through a multistep process involving genetic, epigenetic, inflammatory, and microbiota-related alterations. Polyphenol-rich berries are abundant in anthocyanins, ellagitannins, ellagic acid, quercetin, and related phytochemicals. These compounds target multiple hallmarks of colorectal carcinogenesis. Experimental studies have shown that berry-derived compounds exert anti-proliferative effects by inducing cell-cycle arrest at the G0/G1, S, or G2/M phase. These effects are associated with modulation of cyclin-dependent kinases (CDK), and CDK inhibitors such as p21 and p27. In addition, they inhibit key oncogenic signaling pathways, including Wnt/β-catenin, NF-κB, PI3K/Akt, and ERK/MAPK. Berry phytochemicals also promote programmed cell death. Thus, they activate both intrinsic and extrinsic apoptotic pathways, alter the balance of Bcl-2 family proteins, disrupt mitochondrial integrity, and induce caspase activation. Moreover, berry compounds attenuate chronic inflammation by downregulating expression/production of COX-2, inducible nitric oxide synthase, and pro-inflammatory cytokines through suppression of NF-κB- and STAT3-dependent signaling. Further, they also enhance Nrf2-mediated antioxidant responses. Although parent polyphenols have limited bioavailability, they are extensively metabolized by gut microbiota into bioactive compounds such as protocatechuic acid and urolithins. These metabolites often exhibit comparable or greater anticancer activity and reach physiologically relevant concentrations in the colorectum. Berry polyphenols further modulate gut microbiota composition, promoting beneficial microbes and reinforcing anti-carcinogenic signaling. Altogether, these mechanisms highlight berry-derived compounds as strong candidates for CRC chemoprevention, which merits further clinical investigation.